The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity

Here we report that the widely used protein kinase C inhibitors, bisindolyl maleimide I and IX, are potent inhibitors of glycogen synthase kinase-3 (GS K-3), Bisindolylmaleimide I and IX inhibited GSK-3 in vitro, when assayed e ither in cell lysates (IC50 360 nM and 6.8 nM, respectively) or in GSK-3 be ta immunoprecipitates (IC50 170 nM and 2.8 nM, respectively) derived from r at epididymal adipocytes. Pretreatment of adipocytes with bisindolylmaleimi de I (5 mu M) and IX (2 mu M) reduced GSK-3 activity in total cell lysates, to 25.1 +/- 4.3% and 12.9 +/- 3.0% of control, respectively. By contrast, bisindolylmaleimide V (5 mu M), which lacks the functional groups present o n bisindolylmaleimide I and IX, had little apparent effect. We propose that bisindolylmaleimide I and IX can directly inhibit GSK-3, and that this may explain some of the previously reported insulin-like effects on glycogen s ynthase activity. (C) 1999 Federation of European Biochemical Societies.